Transformation of amino acids into nonracemic 1-(heteroaryl)ethanamines by the enamino ketone methodology

Article abstract of DOI:10.1002/hlca.200690010

N-Protected L-phenylalanines 1a,b were transformed, via the corresponding Weinreb amides 2 and ethynyl ketones 3, into chiral enamino ketones 4 (Scheme 1). Similarly, L-threonine 6 was transformed in four steps into the enamino ketone 10. Cyclocondensatio

Full text of DOI:10.1002/hlca.200690010

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Helvetica Chimica Acta – Vol. 89 (2006)
Transformation of Amino Acids into Nonracemic
1-(Heteroaryl)ethanamines by the Enamino Ketone Methodology
by Samo Pirc, David Bevk, Amalija Golobicˇ, Branko Stanovnik*, and Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, P. O. Box 537,
SI 1001 Ljubljana, Slovenia
(phone: +386611760254; fax: +386611258220; e-mail: jurij.svete@fkkt.uni-lj.si,
branko.stanovnik@fkkt.uni-lj.si)
N-Protected
L
-phenylalanines 1a,b were transformed, via the corresponding Weinreb amides 2 and
-threonine 6 was transformed
ethynyl ketones 3, into chiral enamino ketones 4 (Scheme 1). Similarly,
L
in four steps into the enamino ketone 10. Cyclocondensations of 4 and 10 with pyrazolamines 11, benze-
necarboximidamide (12), and hydrazine derivatives 18 afforded N-protected 1-heteroaryl-2-phenyl-
ethanamines 15a–e, 16, 17, and 21a–k and 1-heteroaryl-1-aminopropan-2-ols 23a,b in good yields
(Schemes 2 and 3). Finally, deprotection by catalytic hydrogenation furnished free amines 22a–g and
24a,b (Scheme 3).
Introduction. – Nonracemic amines and a-amino alcohols represent important
groups of organic compounds, which found a widespread use in various applications,
such as reagents in organic synthesis and resolving agents, chiral auxilliaries and ligands
in asymmetric synthesis (for an illustration, see [1]). A typical example of a synthetic
application of enantiomerically pure a-amino alcohols is their use as chiral catalysts
in asymmetric reactions, such as additions of dialkylzinc to aldehydes (for an illustra-
tion, see [2]) and asymmetric reductions of ketones with borane complexes (for an illus-
tration, see [3]). Such examples are (+)-methylbenzylamine, amphetamine, (+)-ephe-
drine, (1S,2R)-2-amino-1,2-diphenylethanol, and (S)-a,a-diphenylprolinol (Fig. 1).
Fig. 1. Some examples of important 2-phenylethanamines and a-amino alcohols
Recently, a series of alkyl 2-substituted 3-(dimethylamino)prop-2-enoates and
related enamino ketones have been prepared as versatile reagents for the preparation
of various didehydroalanine derivatives, heterocyclic systems, and natural-product ana-
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
31
logs. In extention, chiral cyclic enamino lactams and lactones, derived from a-amino
acids and (+)-camphor have been employed in the synthesis of functionalized hetero-
cycles, such as (heteroaryl)alanines, (heteroaryl)alaninols, (heteroaryl)propanediols, 3-
(heteroaryl)camphors, and heterocyclic compounds with an a-amino acid or dipeptide
structural element incorporated into the ring system (for recent reviews, see [4]; for
recent publications, see [5]). Recently, alkyl 2-substituted 3-(dimethylamino)prop-2-
enoates and related enamino ketones have been employed in a combinatorial synthesis
of heterocycles and N-acyldidehydroalanine esters [6] and in the synthesis of natural-
product analogs, such as aplysinopsins [7] and meridianins [4a][8].
The 3-(dimethylamino)prop-2-enoates and their chiral analogs are usually prepared
by treatment of a suitably functionalized methylene compound with formamide acetal,
e.g., with N,N-dimethylformamide dimethyl acetal or with tert-butoxy-N,N,N’,N’-tetra-
methylmethanediamine (Bredereck’s reagent) [4]. On the other hand, Giacomelli and
co-workers reported the preparation of acyclic chiral enamino ketones from commer-
cially available a-amino acids by treatment of a suitably protected Weinreb amide of an
a-amino acid with (trimethylsilyl)magnesium bromide to give the corresponding silyl
ynone, followed by reaction with Et2NH to afford the enamino ketone. These enamino
ketones were then used in reactions with various a-hydrazino acids and phenylhydra-
zine to afford pyrazole-containing peptidomimetics [9] and a-pyrazoylglycines [10].
Within this context and in continuation of our research in the field of chiral enamino
ketones, we now report the preparation of chiral acyclic enamino ketones 4a,b and 10
from a-amino acids and their utilization in a two-step synthesis of 1-(heteroaryl)-2-phe-
nylethanamines 22 and 1-(heteroaryl)-1-aminopropan-2-ols 24.
Results and Discussion. – First, Weinreb amides 2a,b were prepared from N-pro-
tected -phenylalanines 1a,b according to a known procedure [11]. Treatment of 2a
L
and 2b with ethynylmagnesium bromide followed by quenching excess Grignard
reagent with aqueous NaHSO4 solution afforded the ynones 3a and 3b. Upon reaction
of 3a,b with Et2NH in CH2Cl2 at 08, the desired enamino ketones 4a and 4b were
obtained in 86% and 92% yield, respectively. However, tert-butyl {(1S,3E)-1-benzyl-
4-[methoxy(methyl)amino]-2-oxobut-3-enyl}carbamate (5) was isolated instead of the
expected ynone 3b, when aqueous ammonium chloride was used for quenching of
the reaction mixture obtained upon treatment of 2b with ethynylmagnesium bromide.
This could be explained by initial formation of 3b as the intermediate and N,O-dime-
thylhydroxylamine as the by-product, which undergoes addition to the polarized triple
bond of 3b to give the enamino ketone 5. Similarly, N-[(benzyloxy)carbonyl]- -threo-
L
nine (6) was transformed in three steps into the Weinreb amide 9 according to the lit-
erature procedure [12]. Reaction of 9 with ethynylmagnesium bromide followed by
quenching with aqueous NH4Cl afforded benzyl (4S,5R)-4-{(2E)-3-[methoxy(methyl)-
amino]prop-2-enoyl}-2,2,5-trimethyloxazolidine-3-carboxylate (10) in 73% yield
(Scheme 1, Table).
Cyclocondensations of enamino ketones 4a,b and 10 with 1H-pyrazole-3-amine
(11a), 5-methyl-1H-pyrazole-3-amine (11b), and 3-amino-1H-pyrazole-4-carbonitrile
(11c) in EtOH at 20–808 in the presence of an equimolar amount of aqueous HCl sol-
ution afforded 1-(pyrazolo[1,5-a]pyrimidin-7-yl)-substituted [(1S)-2-phenylethyl]car-
bamates 15a–e and [(1R,2R)-2-hydroxypropyl]carbamate 16 in 20–77% yields.

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
a) ClCOOBu, N-methylmorpholine, AcOEt, 08, then MeNHOMe, 08 ! r.t. b) HCꢀCMgBr, THF,
À788 ! r.t., then aq. NaHSO4 soln. c) Et2NH, CH2Cl2, 08 ! r.t. d) HCꢀCMgBr, THF, À788 ! r.t.,
then aq. NH4Cl soln. e) Me2C(OMe)2, BF3 ·Et2O, r.t. f) MeI, K2CO3, acetone, 08 ! r.t. g) i-PrMgBr,
MeNHOMe, THF, À788 ! À208, then aq. NH4Cl soln.
Under these reaction conditions, 4b did not react with benzenecarboximidamide hydro-
chloride (12). However, in the presence of K2CO3, cyclocondensation took place to
afford tert-butyl [(1S)-2-phenyl-1-(2-phenylpyrimidin-4-yl)ethyl]carbamate (17) in
27% yield. According to the general reactivity of N,N-dimethyl(enamino) ketones
[4], these cyclocondensations can be explained by initial substitution of the diethyl-
amino group followed by condensation with the keto group (Scheme 2, Table).
Next, cyclocondensations of enamino ketones 4a,b and 10 with the hydrazine deriv-
atives hydrazine hydrochloride (18a·HCl), phenylhydrazine hydrochloride (18b·HCl),
(4-nitrophenyl)hydrazine (18c), (4-methoxyphenyl)hydrazine (18d), (2-bromophenyl)-
hydrazine hydrochloride (18e·HCl), 2-hydrazinopyridine (18f), 2-hydrazinopyrimidine
(18g), 6-chloro-3-hydrazinopyridazine (18h), and 3-hydrazino-6-phenylpyridazine (18i)
were studied. When 4a,b were treated with 18a–i in EtOH in the presence of 1 equiv. of
aqueous HCl solution1), N-protected (1S)-2-phenyl-1-pyrazolyl-ethanamines 21a–k
were obtained in 54–98% yields. Also in this case, the reaction can be explained by sub-
stitution of the diethylamino group to give the enehydrazino ketone 19, which cyclizes
into the dihydropyrazole 20, from which H2O is eliminated to give the 2-phenyl-1-pyr-
azolylethanamine 21 [4][13]. Compounds 21a,b, obtained from 4a,b and N2H4 ·HCl
(18a), exist in solution as mixtures of 1H-pyrazol-5-yl and -3-yl isomers 21a,b and
1
)
In the case of hydrazine hydrochlorides 18a,b,e, no aqueous HCl solution was added.

Helvetica Chimica Acta – Vol. 89 (2006)
33
Table. Yields of Enamino Ketones 4a,b, 5, 10, 1H-Pyrazolamines 18a–c, Hydrazine Derivatives 18a–i,
2-Phenylethanamines 15a–e, 17, 21a–k, 22a–g, and a-Amino Alcohols 16, 22a,b, and 24a,b
Reaction
R1
R2
R3
Yield [%]
2a ! 3a ! 4a
2b ! 3b ! 4b
2b ! 5
COOBn
Boc
52a)
83a)
50
73
76
44
32
73
20
77
27
98
86
95
80
70
90
83
89
91
54
78
92
63
92
82
95
98
85
69
70
83
64
9 ! 10
4a+11a ! 15a
4b+11a ! 15b
4a+11b ! 15c
4a+11c ! 15d
4b+11c ! 15e
10+11c ! 16
4a+12 ! 17
4a+18a ! 21a/21’a
4b+18a ! 21b/21’b
4a+18b ! 21c
4a+18c ! 21d
4a+18d ! 21e
4b+18e ! 21f
4a+18f ! 21g
4a+18g ! 21h
4a+18h ! 21i
4b+18h ! 21j
4a+18i ! 21k
10+18b ! 23a
10+18i ! 23b
21a/21’a ! 22a
21c ! 22b
COOBn
Boc
COOBn
COOBn
Boc
COOBn
Boc
COOBn
Boc
COOBn
COOBn
COOBn
Boc
COOBn
COOBn
COOBn
Boc
H
H
H
CN
CN
CN
H
H
Me
H
H
H
H
H
Ph
4-nitrophenyl
4-methoxyphenyl
2-bromophenyl
pyridin-2-yl
pyrimidin-2-yl
6-chloropyridazin-3-yl
6-chloropyridazin-3-yl
6-phenylpyridazin-3-yl
Ph
6-phenylpyridazin-3-yl
H
Ph
4-aminophenyl
4-methoxyphenyl
pyridin-2-yl
pyrimidin-2-yl
6-phenylpyridazin-3-yl
Ph
COOBn
21d ! 22c
21e ! 22d
21g ! 22e
21h ! 22f
21k ! 22g
23a ! 24a
23b ! 24b
6-phenylpyridazin-3-yl
a) Yield over two steps.
21’a,b, respectively. Deprotection of compounds 21c–e,g,h,k by catalytic hydrogena-
tion in the presence of 10% Pd/C afforded the free 2-phenyl-1-pyrazolyl-ethanamines
22a–g in 70–98% yields. Similarly, 1-amino-1-pyrazolyl-propan-2-ols 24a,b were pre-
pared in two steps via 23a,b from enamino ketone 10 (Scheme 3, Table).
1
All novel compounds were characterized by spectroscopic (IR, MS, HR-MS, H-
and 13C-NMR) methods and elemental analyses for C, H, and N. Compounds 3a,b,
4a,b, 5, 10, 15c,d, 21c–e,h, 23a, 22a–g, and 24a,b were not prepared in analytically
pure form. The identities of these compounds were confirmed by HR-EI-MS and
13C-NMR spectra or, in the case of 22a, by FAB-MS and 13C-NMR spectra. The struc-
ture of compound 15b was determined by X-ray diffraction (Fig. 2).

34
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2a)
a) EtOH, 37% aq. HCl soln. (1 equiv.), r.t. ! reflux. b) EtOH, K2CO3, reflux.
Conclusions. – Chiral enamino ketones 4a,b and 10 are available in 3–4 steps from
N-protected
L
-phenylalanines 1a,b and -threonine 6, respectively. They were used effi-
L
ciently as the key reagents in a two-step synthesis of 1-(heteroaryl)-2-phenylethan-
amines 22a–g and 1-amino-1-(heteroaryl)propan-2-ols 24a,b. Due to the wide applica-
bility of 2-substituted alkyl 3-(dimethylamino)propenoates and related enamino
ketones in heterocyclic synthesis and, since related enamino ketones could also be pre-
pared from other commercially available a-amino acids via the corresponding Weinreb
amides, this methodology could be extended also to the preparation of several other
types of 1-(heteroaryl)alkanamines. In comparison with some known synthetic meth-
ods [14–16], especially with the ynone-mediated approach of Knochel and co-workers
[14], the presented enamino ketone methodology is an additional and useful option for
the efficient synthesis of chiral nonracemic 1-(heteroaryl)alkanamines.

Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 3a)
35
a) EtOH, 37% aq. HCl soln. (1 equiv.), r.t. ! reflux. b) H2 (1 bar), EtOH and/or THF, 10% Pd/C,
r.t.
The financial support from the Slovenian Research Agency through grants P0-0502-0103, P1-0179,
and J1-6689-0103-04 is gratefully acknowledged. The authors wish to express their gratitude to the
Alexander von Humboldt Foundation, Germany, for the donation of a Büchi medium-pressure liquid
chromatograph. The diffraction data for compound 15b were collected in the Laboratory of Inorganic
Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. We
acknowledge the financial contribution of the Ministry of Science and Technology, Republic of Slovenia,
through grants X-2000 and PS-511-103, which thus made the purchase of the apparatus possible.
Experimental Part
1. General. N-[(Benzyloxy)carbonyl]-L-phenylalanine (1a), N-[(tert-butoxy)carbonyl]-L-phenylala-
nine (1b), N-[(benzyloxy)carbonyl]- -threonine (6), 1H-pyrazolamines 11a–c, and hydrazines 18a–f
L
are commercially available (Fluka AG and Sigma-Aldrich). Weinreb amides 2a,b [11] and 9 [12], 2-hydra-
zinopyrimidine (18g) [17], 6-chloro-3-hydrazinopyridazine (18h) [18], and 3-hydrazino-6-phenylpyrida-
zine (18i) [19] were prepared according to the published procedures. All starting materials were commer-
cially available (in most cases from Fluka) and purified following the standard techniques. Column chro-
matography (CC): silica gel 60 (0.04–0.06 mm; Fluka). Medium-pressure liquid chromatography

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Helvetica Chimica Acta – Vol. 89 (2006)
Fig. 2. ORTEP View of the asymmetric unit of compound 15b. Arbitrary atom numbering. Ellipsoids
at the 50% probability level.
(MPLC): Büchi isocratic system with detection2); silica gel 60 (0.015–0.035 mm; Merck); 15×460 mm
column (dry filled); backpressure 10–15 bar; UV detection at 254 nm; 100–150 mg of sample per run.
TLC: aluminium foils coated with silica gel 60 F 254 (0.2 mm; Merck). M.p.: Kofler micro hot stage. Opti-
cal rotations: Perkin-Elmer-241-MC polarimeter. IR: Perkin-Elmer-Spectrum-BX-FTIR spectophotom-
eter; in cmÀ1 1H-(300 MHz) and 13C-NMR (75.5 MHz): Bruker-Avance-DPX-300 spectrometer; d in
.
ppm rel. to Me4Si as internal standard (=0 ppm), J in Hz. MS: Autospeck-Q (VG-Analytical) spectrom-
eter; in m/z. Elemental analyses: Perkin-Elmer-CHN-2400-II analyzer.
2. Ethynyl Ketones 3a,b: General Procedure. At À788, 0.5
was added slowly to the stirred soln. of 2 (10 mmol) in anh. THF (20 ml) under Ar, and the resulting mix-
ture was stirred at À788 for 1 h and at r.t. for 12 h. The mixture was poured into cold (08) 1 aq. NaHSO4
(150 ml) and stirred for 1 h. THF was evaporated at 35–408 and the aq. residue extracted with Et2O
(2×150 ml). The combined org. phase was washed successively with 1 aq. NaHSO4 (150 ml), sat. aq.
M
(HCꢀCMgBr in THF 80 ml, 40 mmol)
M
M
NaHCO3 soln. (150 ml), and brine (150 ml), dried (Na2SO4), and evaporated and the residue purified
by CC (AcOEt/hexanes): 3a,b.
Benzyl [(1S)-1-Benzyl-2-oxobut-3-ynyl]carbamate (3a). From 2a (3.2 g, 9.3 mmol), after CC
(AcOEt/hexanes 1:3): 1.74 g (61%) of 3a. Oil. [a]2D3 =+1.27 (c=1.05, CHCl3). IR (NaCl): 3404, 3270,
1
3031, 2093 (CꢀC), 1687 (C=O), 1497, 1455, 1254, 1045, 697. H-NMR (CDCl3): 3.20 (dd, J=6.0, 14.3,
1 H of PhCH2); 3.29 (dd, J=5.7, 14.3, 1 H of PhCH2); 3.39 (s, HÀC(1)); 4.71–4.80 (m, HÀC(4)); 5.09
(s, PhCH2O); 5.22 (d, J=7.2, NH); 7.09–7.15 (m, 2 H of Ph); 7.22–7.40 (m, 8 H of Ph). 13C-NMR
(CDCl3): 37.1; 62.8; 67.5; 80.1; 83.1; 127.7; 128.5; 128.7; 128.9; 129.1; 129.8; 135.5; 136.6; 156.1; 185.4.
EI-MS: 307 (M+). EI-HR-MS: 307.12060 (C19H17N1Oþ3 , M+; calc. 307.120844).
tert-Butyl [(1S)-1-Benzyl-2-oxobut-3-ynyl]carbamate (3b). From 2b (2.5 g, 8.1 mmol), after CC
(AcOEt/hexanes 1:5): 2.0 g (90%) of 3b. Oil. [a]2D2 =+8.66 (c=1.73, CHCl3). IR (NaCl): 3354, 3268,
2979, 2093 (CꢀC), 1711 (C=O), 1688 (C=O), 1497, 1456, 1367, 1252, 1165, 1048, 700. 1H-NMR
(CDCl3): 1.41 (s, t-BuO); 3.16 (dd, J=5.7, 14.3, HaÀC(5)); 3.27 (dd, J=5.7, 14.3, HbÀC(5)); 3.39 (s,
2
)
Donation of the Alexander von Humboldt Foundation, Germany.

Helvetica Chimica Acta – Vol. 89 (2006)
37
HÀC(1)); 4.62–4.73 (m, HÀC(4)); 4.97 (d, J=6.8, NH); 7.13–7.19 (m, 2 H of Ph); 7.21–7.39 (m, 3 H of
Ph). 13C-NMR (CDCl3): 28.7; 37.2; 62.4; 80.3; 80.6; 82.6; 127.6; 129.0; 129.8; 135.7; 155.4; 186.0. FAB-
MS: 274 ([M+H]+).
3. Alkyl [(1S,3E)-1-Benzyl-4-(diethylamino)-2-oxobut-3-enyl]carbamates 4a,b: General Procedure
Et2NH (0.73 ml, 5.2 mmol) was added to a cooled (08) soln. of 3a,b (5 mmol) in CH2Cl2 (35 ml), and
the soln. was stirred at r.t. for 12 h. Volatile components were evaporated, and the residue was purified
by CC (AcOEt/hexanes 2 :1): 4a,b.
Benzyl [(1S,3E)-1-Benzyl-4-(diethylamino)-2-oxobut-3-enyl]carbamate (4a). From 3a (1.2 g, 3.9
mmol) and Et2NH (0.55 ml): 1.28 g (86%) of 4a. Oil. [a]2D1 =+34.4 (c=1.13, CHCl3). IR (NaCl): 3397,
3292, 2976, 1717 (C=O), 1649, 1565, 1497, 1365, 1281, 1045, 699. 1H-NMR (CDCl3): 1.03, 1.18 (2 m,
1:1, 2 MeCH2); 2.92–3.16 (m, MeCH2, HaÀC(5), HbÀC(5)); 3.21 (br. s, MeCH2); 4.49–4.62 (m, HÀ
C(4)); 4.85 (d, J=12.4, HÀC(2)); 5.09 (s, PhCH2O); 5.80 (br. d, J=6.8, NH); 7.09–7.24 (m, Ph);
7.28–7.39 (m, Ph); 7.49 (br. s, HÀC(1)). 13C-NMR (CDCl3): 11.8; 15.0; 40.4; 43.0; 50.9; 66.8; 126.8;
128.28; 128.30, 128.6; 128.8; 130.0; 137.2; 137.9; 151.8; 156.1; 193.5. EI-MS: 380 (M+). EI-HR-MS:
380.210870 (C23H28N2Oþ3 , M+; calc. 380.209993).
tert-Butyl [(1S,3E)-1-Benzyl-4-(diethylamino)-2-oxobut-3-enyl]carbamate (4b). From 3b (1.7 g, 6.2
mmol) and Et2NH (0.9 ml): 1.98 g (92%) of 4b. Oil. [a]2D1 =+32.3 (c=0.75, CHCl3). IR(NaCl): 3412,
2976, 2932, 1709 (C=O), 1649, 1568, 1468, 1366, 1283, 1170, 1047, 776, 701. 1H-NMR (CDCl3): 1.04,
1.17 (2m, 1:1, 2 MeCH2); 1.41 (s, t-Bu); 2.91–3.14 (m, MeCH2, PhCH2); 3.21 (br. s, MeCH2);
4.45–4.56 (m, HÀC(4)); 4.85 (d, J=12.8, HÀC(2)); 5.53 (br. d, J=7.2, NH); 7.12–7.26 (m, Ph); 7.48
(br. s, HÀC(1)). 13C-NMR (CDCl3): 11.8; 15.0; 28.8; 40.6; 42.9; 50.9; 79.4; 126.7; 128.5; 130.0; 138.2;
151.7; 155.7; 194.1. EI-MS: 346 (M+). EI-HR-MS: 346.225013 (C20H30N2Oþ3 , M+; calc. 346.225643).
4. N-Methoxy-N-methyl(enamino) Ketones
5
and 10: General Procedure. At À788, 0.5
M
(HCꢀCMgBr in THF 80 ml, 40 mmol) was added slowly to a stirred soln. of 2b or 9 (10 mmol) in anh.
THF (20 ml) under Ar, and the mixture was stirred at À788 for 1 h and at r.t for 12 h. The mixture
was poured into cold (08) sat. aq. NH4Cl soln. (100 ml) and stirred at r.t. for 1 h. THF was then evaporated
at ca. 308, and the aq. residue was extracted with Et2O (2×150 ml). The combined org. phase was washed
successively with 1M aq. NaHSO4 (150 ml), sat. aq. NaHCO3 soln. (150 ml), and brine (150 ml), dried
(Na2SO4), and evaporated and the residue purified by CC (AcOEt/hexanes 1:1): 5 or 10.
tert-Butyl {(1S,3E)-4-[Methoxy(methyl)amino]-2-oxobut-3-enyl}carbamate (5). From 2b (2.5 g, 8.1
mmol): 1.35 g (50%) of 5. Oil. [a]2D1 =+100.8 (c=0.52, CHCl3). IR (NaCl): 3414, 3323, 2975, 1709
(C=O), 1657, 1578, 1493, 1366, 1170, 1046, 1012, 701. 1H-NMR (CDCl3): 1.41 (s, t-BuO); 3.00–3.06
(m, PhCH2); 3.10 (s, MeN); 3.58 (s, MeO); 4.51–4.59 (m, HÀC(4)); 5.26 (d, J=12.8, HÀC(2)); 5.42
(d, J=7.5, NH); 7.15–7.29 (m, Ph); 7.35 (d, J=12.4, HÀC(1)). 13C-NMR (CDCl3): 28.8; 39.8; 39.9;
59.2; 60.1; 79.6; 95.1; 126.8; 128.6; 130.0; 137.7; 148.4; 155.6; 195.2. EI-MS: 335 ([M+H]+). FAB-MS:
335 ([M+H]+). EI-HR-MS: 335.198060 (C18H27N2Oþ4 , [M+H]+; calc. 335.197083).
Benzyl (4S,5R)-4-{(2E)-3-[Methoxy(methyl)amino]prop-2-enoyl]-2,2,5-trimethyloxazolidine-3-car-
boxylate (10). From 9 (4.77 g, 14.2 mmol): 3.73 g (73%) of 10. Oil. [a]2D5 =À35.7 (c=1.00, CHCl3). IR
1
(NaCl): 2982, 1708 (C=O), 1663, 1579, 1410, 1350, 1123, 1072, 988, 696. H-NMR ((D6)DMSO, 808):
1.30 (d, J=6.0, MeÀC(5)); 1.52, 1.55 (2s, 1:1, 2 MeÀC(2)); 3.17 (s, MeN); 3.58 (s, MeO); 3.89–3.99
(m, HÀC(5)); 4.07 (d, J=7.5, HÀC(4)); 4.98 (s, PhCH2O); 5.30 (d, J=12.4, CH=CHNMe); 7.21–7.36
(m, Ph); 7.48 (d, J=12.4, CH=CHNMe). 13C-NMR ((D6)DMSO, 808): 19.9; 25.4; 27.7; 39.9; 60.0;
66.8; 71.1; 75.3; 93.7; 95.0; 128.3; 128.4; 129.0; 137.4; 149.0; 152.5; 192.6. EI-MS: 363 ([M+H]+). EI-
HR-MS: 363.193002 (C19H27N2Oþ5 , [M+H]+; calc. 363.191997).
5. Compounds 15a–e, 21a–k, and 23a,b. General Procedure A (G.P. A). A mixture of 4a,b or 10 (0.5
mmol), hydrazine derivative 18 (0.5 mmol), EtOH (4 ml), and 37% aq. HCl soln.1) (2 drops, ca. 0.6
mmol) was slowly heated up and then refluxed for 1.5–6 h. After cooling the precipitate was collected
by filtration and washed with cold (08) EtOH and Et2O. Compounds 21g,i–k and 23b were prepared
in this manner.
General Procedure B (G.P. B). A mixture of 4a,b or 10 (0.5 mmol), 1H-pyrazolamine 11 or hydrazine
derivative 18a–i (0.5 mmol), EtOH (4 ml), and 37% aq. HCl1) soln. (2 drops, ca. 0.6 mmol) was stirred at
20–808 for 2–48 h. Volatile components were evaporated, and the residue was purified by CC. Com-
pounds 15a–e, 21a–f,h, and 23a were prepared in this manner.

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Helvetica Chimica Acta – Vol. 89 (2006)
Benzyl [(1S)-2-Phenyl-1-(pyrazolo[1,5-a]pyrimidin-7-yl)ethyl]carbamate (15a). From 4a (0.190 g, 0.5
mmol) and 11a (0.042 g, 0.5 mmol) by G.P. B (stirring at 808 for 5 h). CC (AcOEt/hexanes 1:2) gave
0.142 g (76%) of 15a. M.p. 155–1578 (from EtOH). [a]2D2 =+64.7 (c=0.44, CHCl3). IR (KBr): 3311,
1683 (C=O), 1615, 1537, 1454, 1272, 1089, 1057, 1022, 745, 703. 1H-NMR (CDCl3): 3.37 (dd, J=7.1,
13.3, HaÀC(2)); 3.53 (dd, J=8.1, 13.3, HbÀC(2)); 5.01, 5.09 (2d, J=12.1, PhCH2O); 5.40–5.51 (m, HÀ
C(1)); 6.42 (d, J=4.1, HÀC(6’)); 6.57 (br. d, J=9.0, NH); 6.76 (d, J=2.3, HÀC(3’)); 6.90–6.99 (m, 2
H of Ph); 7.15–7.22 (m, 3 H of Ph); 7.26–7.37 (m, Ph); 8.18 (d, J=2.3, HÀC(2’)); 8.29 (d, J=4.1, HÀ
C(5’)). 13C-NMR (CDCl3): 38.1; 54.8; 67.1; 97.0; 106.4; 127.0; 128.1; 128.2; 128.5; 128.6; 129.0; 136.1;
136.4; 144.5; 145.9; 149.0; 149.3; 155.6. EI-MS: 372 (M+). EI-HR-MS: 372.159560 (C22H20N4O2þ, M+;
calc. 372.158626). Anal. calc. for C22H20N4O2 (372.42): C 70.95, H 5.41, N 15.04; found: C 70.80, H
5.47, N 15.08.
tert-Butyl [(1S)-2-Phenyl-1-(pyrazolo[1,5-a]pyrimidin-7-yl)ethyl]carbamate (15b). From 4b (0.173 g,
0.5 mmol) and 11a (0.042 g, 0.5 mmol) by G.P. B (stirring at 208 for 48 h). CC (AcOEt/hexanes 1:2) gave
0.074 g (44%) of 15b. M.p. 141–1448. [a]2D4 =+54.6 (c=0.50, CHCl3). IR (KBr): 3346, 1686 (C=O), 1616,
1526, 1456, 1274, 1169, 820, 704. 1H-NMR (CDCl3): 1.38 (s, t-BuO); 3.32 (dd, J=6.8, 13.2, HaÀC(2)); 3.51
(dd, J=7.9, 13.2, HbÀC(2)); 5.37–5.47 (m, HÀC(1)); 6.22 (br. d, J=6.4, NH); 6.43 (br. d, J=3.0, HÀ
C(6’)); 6.76 (d, J=2.3, HÀC(3’)); 6.92–7.00 (m, 2 H of Ph); 7.16–7.22 (m, 3 H of Ph); 8.20 (d, J=2.3,
HÀC(2’)); 8.30 (br. d, J=3.0, HÀC(5’)). 13C-NMR (CDCl3): 28.3; 38.2; 54.1; 80.2; 96.9; 106.3; 126.9;
128.5; 129.0; 136.6; 144.5; 146.5; 149.0; 149.3; 154.9. Anal. calc. for C19H22N4O2 (338.40): C 67.44, H
6.55, N 16.56; found: C 67.71, H 6.77, N 16.52.
Benzyl [(1S)-1-(2-Methylpyrazolo[1,5-a]pyrimidin-7-yl)-2-phenylethyl]carbamate (15c). From 4a
and (0.190 g, 0.5 mmol) and 11b (0.049 g, 0.5 mmol) by G.P. B (stirring at 208 for 48 h). CC (AcOEt/hex-
anes 2 :3) gave 0.060 g (32%) of 15c. M.p. 169–1738. [a]2D5 =+49.9 (c=0.40, CHCl3). IR(KBr): 3458,
3309, 1685, 1613, 1536, 1268, 740, 696. 1H-NMR (CDCl3): 2.56 (s, MeÀC(2’)); 3.36 (dd, J=7.0, 13.2,
HaÀC(2)); 3.52 (dd, J=7.9, 13.2, HbÀC(2)); 5.02, 5.10 (2d, J=12.1, PhCH2O); 5.34–5.45 (m, HÀ
C(1)); 6.31 (d, J=4.1, HÀC(6’)); 6.51 (s, HÀC(3’)); 6.64 (br. d, J=8.7, NH); 6.90–7.00 (m, 2 H of
Ph); 7.14–7.22 (m, 3 H of Ph); 7.27–7.40 (m, Ph); 8.20 (d, J=4.1, HÀC(5’)). 13C-NMR (CDCl3): 15.2;
38.6; 55.3; 67.5; 77.3; 96.6; 106.0; 127.4; 128.6; 129.0; 129.5; 136.6; 136.9; 137.2; 145.6; 149.1; 150.5;
155.4; 156.1. EI-MS: 386 (M+). EI-HR-MS: 386.175060 (C23H22N4O2, M+; calc. 386.174276).
Benzyl [(1S)-1-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)-2-phenylethyl]carbamate (15d). From 4a
(0.190 g, 0.5 mmol) and 11c (0.054 g, 0.5 mmol) by G.P. B (stirring at 808 for 4 h). CC (CHCl3/MeOH
60 :1) gave 0.145 g (73%) of 15d. M.p. 85–898. [a]2D1 =+55.46 (c=0.61, CHCl3). IR (KBr): 3343, 2230
1
(CꢀN), 1696 (C=O), 1620, 1552, 1527, 1264, 1217, 1057, 737, 698. H-NMR (CDCl3): 3.31 (dd, J=7.3,
13.4, HaÀC(2)); 3.48 (dd, J=7.4, 13.7, HbÀC(2)); 4.97–5.10 (m, PhCH2O); 5.51–5.61 (m, HÀC(1));
6.06 (br. d, J=8.6, NH); 6.73 (d, J=4.5, HÀC(6’)); 6.91–6.97 (m, 2 H of Ph); 7.20–7.25 (m, 3 H of
Ph); 7.26–7.39 (m, Ph); 8.46 (s, HÀC(2’)); 8.55 (d, J=4.5, HÀC(5’)). 13C-NMR (CDCl3): 38.4; 54.4;
67.8; 83.9; 109.3; 112.9; 127.9; 128.6; 128.8; 129.0; 129.25; 129.29; 135.9; 136.2; 147.5; 149.1; 151.1;
153.1; 155.9. EI-MS: 397 (M+). FAB-MS: 398 ([M+H]+). EI-HR-MS: 397.154250 (C23H19N5Oþ2 , M+;
calc. 397.153875).
tert-Butyl [(1S)-1-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)-2-phenylethyl]carbamate (15e). From 4b
(0.173 g, 0.5 mmol) and 11c (0.054 g, 0.5 mmol) by G.P. B (stirring at 208 for 24 h). CC (AcOEt/hexanes
1:2) gave 0.036 g (20%) of 15e. M.p. 149–1528. [a]2D4 =+55.7 (c=0.50, CHCl3). IR (KBr): 3362, 2231
(CꢀN), 1712 (C=O), 1620, 1553, 1518, 1368, 1250, 1168, 701. 1H-NMR (CDCl3): 1.38 (s, t-BuO);
3.20–3.32 (m, HaÀC(2)); 3.46 (dd, J=7.2, 13.6, HbÀC(2)); 5.49–5.58 (m, HÀC(1)); 5.73 (br. s, NH);
6.75 (br. d, J=3.8, HÀC(6’)); 6.92–7.01 (m, 2 H of Ph); 7.18–7.25 (m, 3 H of Ph); 8.47 (s, HÀC(2’));
8.57 (br. d, J=3.8, HÀC(5’)). 13C-NMR (CDCl3): 28.7; 38.6; 53.9; 81.3; 83.9; 109.1; 113.0; 127.9; 129.3;
192.4; 136.1; 147.6; 149.9; 151.2; 153.1; 155.2. Anal. calc. for C20H21N5O2 (363.41): C 66.10, H 5.82, N
19.27; found: C 66.04, H 6.08, N 18.98.
Benzyl [(1S)-2-Phenyl-1-(1H-pyrazol-5-yl)ethyl]carbamate (21a) and Benzyl [(1S)-2-Phenyl 1-(1H-
pyrazol-3-yl)ethyl]carbamate (21’a). From 4a (0.190 g, 0.5 mmol) and 18a (0.035 g, 0.5 mmol) by G.P. B
(stirring at 808 for 6 h). CC (CHCl3/MeOH 30 :1) gave 0.158 g (98%) of 21a/21’a 72 :28. M.p.
122–1388 (CH2Cl2/hexane). [a]2D2 =À21.7 (c=0.62, CHCl3). IR (KBr): 3356, 1693 (C=O), 1537, 1455,
1249, 1040, 744, 701. 1H-NMR (CDCl3): 3.18 (d, J=6.0, HÀC(2)); 4.97–5.21 (m, HÀC(1)); 5.08 (s,

Helvetica Chimica Acta – Vol. 89 (2006)
39
PhCH2O); 5.60 (br. s, NH); 6.05 (s, HÀC(4’)); 6.75 (br. s, HÀN(1’)); 7.00–7.14 (m, 2 H of Ph); 7.15–7.24
1
(m, 3 H of Ph); 7.27–7.47 (m, Ph, HÀC(3’)). H-NMR ((D6)DMSO): 2.95 (dd, J=9.8, 13.6, HaÀC(2));
3.03–3.16 (m, HbÀC(2)); 4.82–5.01 (m, PhCH2O, HÀC(1)); 6.18 (s, HÀC(4’)); 7.14–7.38 (m, 2 Ph);
7.61 (s, HÀC(3’)); 7.43 (br. s, NH (21’a)); 7.64 (br. s, NH (21a)); 12.52 (br. s, HÀN(1’) (21a)); 12.65
(br. s, HÀN(1’) (21’a)). EI-MS: 322 ([M+H]+). EI-HR-MS: 322.156050 (C19H20N3Oþ2 , ([M+H]+);
calc. 322.155552). Anal. calc. for C19H19N3O2 (321.37): C 71.07, H 5.96, N 13.08; found: C 70.95, H
6.04, N, 13.08.
tert-Butyl [(1S)-2-Phenyl-1-(1H-pyrazol-5-yl)ethyl]carbamate (21b) and tert-Butyl [(1S)-2-Phenyl-1-
(1H-pyrazol-3-yl)ethyl]carbamate (21’b). From 4b (0.173 g, 0.5 mmol) and 18a (0.034 g, 0.5 mmol) by
G.P. B (stirring at 808 for 6 h). CC (CHCl3/MeOH 40 :1) gave 0.124 g (86%) of 21b/21’b 87:13. M.p.
113–1158. [a]2D1 =À28.7 (c=0.65, CHCl3). IR (KBr): 3379, 2978, 1690 (C=O), 1518, 1366, 1247, 1171,
1
1023, 800, 700. H-NMR (CDCl3): 1.40 (s, t-BuO); 3.16 (d, J=5.7, HÀC(2)); 5.06 (br. d, J=5.7, HÀ
C(1)); 5.20 (br. s, NH); 6.05 (s, HÀC(4’)); 6.40 (br. s, HÀN(1’)); 7.08–7.14 (m, 2 H of Ph); 7.15–7.28
(m, 3 H of Ph); 7.45 (d, J=1.9, HÀC(3’)). 1H-NMR ((D6)DMSO): 1.19 (s, t-BuO (21’b)); 1.29 (s, t-
BuO (21b)); 2.92 (dd, J=9.4, 13.2, HaÀC(2)); 3.05 (dd, J=5.3, 13.2, HbÀC(2)); 4.82 (br. s, HÀC(1));
6.16 (s, HÀC(4’) (21b)); 6.67 (br. s, HÀC(4’) (21’b)); 7.02–7.37 (m, Ph, HÀC(3’)); 7.59 (s, NH); 12.48
(br. s, HÀN(1’) (21b)); 12.56 (br. s, HÀN(1’) (21’b)). 13C-NMR (CDCl3): 28.3; 41.7 (21b); 44.4 (21’b);
49.8 (21b); 52.1 (21’b); 79.7; 103.2; 126.4; 128.2; 129.5; 131.8; 137.5; 150.3 (21b); 151.1 (21’b); 155.5
(21’b); 156.1 (21b). Anal. calc. for C16H21N3O2 (287.36): C 66.88, H 7.37, N 14.62; found: C 67.18, H
7.61, N 14.61.
Benzyl [(1S)-2-Phenyl-1-(1-phenyl-1H-pyrazol-5-yl)ethyl]carbamate (21c). From 4a (0.190 g, 0.5
mmol) and 18b (0.073 g, 0.5 mmol) by G.P. B (stirring at 808 for 6 h). CC (AcOEt/hexanes 1:2) gave
0.189 g (95%) of 21c. Oil. [a]2D1 =+12.2 (c=1.50, CHCl3). IR (NaCl): 3310, 3063, 3031, 1713 (C=O),
1
1599, 1530, 1503, 1454, 1399, 1250, 1028, 697. H-NMR (CDCl3): 2.90 (dd, J=7.5, 13.3, HaÀC(2)); 3.00
(dd, J=5.8, 13.2, HbÀC(2)); 4.95–5.20 (m, HÀC(1), NH, PhCH2O); 6.31 (d, J=1.9, HÀC(4’));
6.83–6.89 (m, 2 H of Ph); 7.11–7.23 (m, 5 H of Ph); 7.26–7.40 (m, 8 H of Ph); 7.60 (d, J=1.9, HÀ
C(3’)). 13C-NMR (CDCl3): 42.7; 49.4; 67.4; 104.9; 126.3; 127.3; 128.5; 128.6; 128.81; 128.84; 129.0;
129.5; 129.7; 136.4; 136.6; 139.6; 140.3; 144.3; 155.6. EI-MS: 398 ([M+H]+). FAB-MS: 398 ([M+H]+).
EI-HR-MS: 398.187950 (C25H24N3Oþ2 , [M+H]+; calc. 398.186852).
Benzyl {(1S)-1-[1-(4-Nitrophenyl)-1H-pyrazol-5-yl]-2-phenylethyl}carbamate (21d). From 4a (0.190
g, 0.5 mmol), 18c (0.077 g, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol) by G.P. B (stirring
at 808 for 1.5 h). CC (AcOEt/hexanes 1:2) gave 0.177 g (80%) of 21d. Oil. [a]2D4 =+71.2 (c=0.612,
CHCl3). IR (KBr): 3317, 3031, 1711 (C=O), 1598, 1522, 1503, 1342, 1246, 1111, 1026, 855, 698. 1H-
NMR (CDCl3): 2.89 (dd, J=8.7, 12.8, HaÀC(2)); 3.10 (dd, J=4.9, 13.2, HbÀC(2)); 5.06 (s, PhCH2O);
5.08–5.20 (m, HÀC(1), NH); 6.45 (d, J=1.9, HÀC(4’)); 6.79–6.84 (m, 2 H of C6H4); 7.08–7.21 (m, 4
H of Ph); 7.27–7.41 (m, 6 H of Ph); 7.67 (d, J=1.9, HÀC(3’)); 8.10–8.23 (m, 2 H of C6H4). 13C-NMR
(CDCl3): 43.3; 49.6; 67.5; 106.2; 124.8; 126.5; 127.6; 128.5; 128.8; 128.95, 129.05, 129.5; 136.1; 136.5;
141.6; 144.6; 145.2; 147.1; 155.9. EI-MS: 443 ([M+H]+). EI-HR-MS: 443.172680 (C25H23N4O4þ,
[M+H]+; calc. 443.171931).
Benzyl {(1S)-1-[1-(4-Methoxyphenyl)-1H-pyrazol-5-yl]-2-phenylethyl}carbamate (21e). From 4a
(0.190 g, 0.5 mmol) and 18d (0.087 g, 0.5 mmol) by G.P. B (stirring at 808 for 3 h). CC (AcOEt/hexanes
1:2) gave 0.150 g (70%) of 21e. Oil. [a]2D1 =+11.6 (c=1.74, CHCl3). IR (NaCl): 3312, 3031, 2936, 1716
(C=O), 1518, 1455, 1251, 1028, 837, 699. 1H-NMR (CDCl3): 2.91 (dd, J=7.5, 13.2, HaÀC(2));
2.96–3.06 (m, HbÀC(2)); 3.82 (s, MeO); 5.03 (m, HÀC(1), NH, PhCH2O); 6.28 (d, J=1.9, HÀC(4’));
6.80–6.91 (m, 2 H of C6H4); 7.00–7.11 (m, 2 H of Ph); 7.13–7.21 (m, 2 H of C6H4); 7.26–7.40 (m,
Ph); 7.57 (d, J=1.9, HÀC(3’)). 13C-NMR (CDCl3): 42.7; 49.4; 55.9; 67.3; 104.4; 114.6; 127.3; 127.8;
128.5; 128.6; 128.8; 128.9; 129.7; 132.6; 136.5; 136.6; 139.9; 144.3; 155.6; 159.9. EI-MS: 428 ([M+H]+).
HR-MS: 428.198300 (C26H26N3Oþ3 , [M+H]+; calc. 428.197417).
tert-Butyl {(1S)-1-[1-(2-Bromophenyl)-1H-pyrazol-5-yl]-2-phenylethyl}carbamate (21f). From 4b
(0.173 g, 0.5 mmol) and 18e (0.112 g, 0.5 mmol) by G.P. B (stirring at 808 for 2 h). CC (AcOEt/hexanes
1:2) gave 0.199 g (90%) of 21f. M.p. 39–458. [a]2D1 =À57.4 (c=0.53, CHCl3). IR (KBr): 3273, 2976, 1703
(C=O), 1494, 1455, 1366, 1248, 1169, 1019, 928, 763, 698. 1H-NMR ((D6)DMSO, 808): 1.16 (s, t-BuO); 2.93
(br. d, J=8.3, CH2(2)); 4.53–4.63 (m, HÀC(1)); 6.51 (d, J=1.5, HÀC(4’)); 6.88 (br. s, NH); 6.94–7.02 (m,

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Helvetica Chimica Acta – Vol. 89 (2006)
2 H of Ph); 7.10–7.24 (m, 3 H of Ph, 1 H of C6H4); 7.41–7.52 (m, 2 H of C6H4); 7.58 (d, J=1.5, HÀC(3’));
7.76–7.82 (m, 1 H of C6H4). Anal. calc. for C22H24BrN3O2 (442.35): C 59.73; H 5.47; N 9.50; found: C
59.66, H 5.60, N 9.46.
Benzyl {(1S)-2-Phenyl-1-[1-(pyridin-2-yl)-1H-pyrazol-5-yl]ethyl}carbamate (21g). From 4a (0.190 g,
0.5 mmol), 18f (0.054 g, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol) by G.P. A (reflux
for 3 h): 0.165 g (83%) of 21g. M.p. 165–1668. [a]2D4 =+20.3 (c=0.80, CHCl3). IR (KBr): 3334, 1687
(C=O), 1594, 1543, 1475, 1436, 1387, 1261, 1028, 801, 779, 743, 699. 1H-NMR (CDCl3): 3.08 (dd,
J=7.9, 13.7, HaÀC(2)); 3.17 (dd, J=7.4, 13.7, HbÀC(2)); 5.04 (s, PhCH2O); 5.74–5.85 (m, HÀC(1));
6.21 (d, J=1.5, HÀC(4’)); 6.63 (br. d, J=7.2, NH); 6.99–7.06 (m, 2 H of Ph); 7.13–7.22 (m, 3 H of
Ph); 7.25 (ddd, J=1.0, 5.0, 8.3, HÀC(5’’)); 7.26–7.37 (m, 5 H of Ph); 7.55 (d, J=1.5, HÀC(3’)); 7.86
(‘dt’, J=1.8, 8.2, HÀC(4’’)); 7.99 (br. d, J=8.1, HÀC(3’’)); 8.49 (br. d, J=4.5, HÀC(3’’)). 13C-NMR
(CDCl3): 41.3; 50.6; 67.0; 109.6; 116.8; 122.1; 127.0; 128.4; 128.7; 128.9; 129.6; 137.0; 137.9; 139.4;
141.1; 144.7; 147.6; 153.7; 156.1. EI-MS: 398 (M+). EI-HR-MS: 398.175250 (C24H22N4O2þ, M+; calc.
398.174276). Anal. calc. for C24H22N4O2 (398.46): C 72.34, H 5.75, N 14.06; found: C 72.61, H 5.63, N
13.72.
Benzyl {(1S)-2-Phenyl-1-[1-(pyrimidin-2-yl)-1H-pyrazol-5-yl]ethyl}carbamate (21h). From 4a (0.190
g, 0.5 mmol), 18g (0.055 g, 0.5 mmol), and 37%(aq. HCl soln. 2 drops, ca. 0.6 mmol) by G.P. B (stirring at
808 for 3 h). CC (AcOEt) gave 0.177 g (89%) of 21h. M.p. 139–1428. [a]2D1 =+23.9 (c=1.00, CHCl3). IR
(KBr): 3442, 3329, 1696 (C=O), 1573, 1541, 1422, 1258, 1027, 921, 737, 696. 1H-NMR (CDCl3): 2.98–3.13
(m, HaÀC(2)); 3.22 (dd, J=6.0, 13.9, HbÀC(2)); 5.03 (s, PhCH2O); 5.82 (br. d, J=7.1, NH); 5.98–6.07 (m,
HÀC(1)); 6.28 (d, J=1.5, HÀC(4’)); 7.03–7.11 (m, 2 H of Ph); 7.17–7.37 (m, 8 H of Ph, HÀC(5’’)); 7.68
(d, J=1.5, HÀC(3’)); 8.81 (d, J=4.5, HÀC(4’’), HÀC(6’’)). 13C-NMR (CDCl3): 41.1; 50.1; 66.7; 109.4;
118.6; 126.7; 128.0; 128.37, 128.41, 129.2; 136.4; 136.8; 142.0; 146.1; 155.5; 157.2; 158.6. EI-MS: 399
(M+). EI-HR-MS: 399.170620 (C23H21N5O2þ, M+; calc. 399.169525).
Benzyl {(1S)-1-[1-(6-Chloropyridazin-3-yl)-1H-pyrazol-5-yl]-2-phenylethyl}carbamate (21i). From
4a (0.190 g, 0.5 mmol), 18h (0.073 mg, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol) by
G.P. A (reflux for 3 h): 0.197 g (91%) of 21i. M.p. 181–1848 (EtOH). [a]2D4 =+22.5 (c=1.00, CHCl3).
1
IR (KBr): 3338, 1694 (C=O), 1539, 1467, 1425, 1256, 1027, 921, 698. H-NMR (CDCl3): 3.11–3.22 (m,
HaÀC(2)); 3.30 (dd, J=6.4, 13.9, HbÀC(2)); 5.00 (s, PhCH2O); 5.75–5.86 (m, HÀC(1)); 6.11 (br. d,
J=7.9, NH); 6.33 (d, J=1.5, HÀC(4’)); 7.07–7.13 (m, 2 H of Ph); 7.18–7.36 (m, 8 H of Ph); 7.63 (br.
d, J=8.7, HÀC(5’’)); 7.64 (d, J=1.5, HÀC(3’)); 8.23 (d, J=8.7, HÀC(4’’)). 13C-NMR (CDCl3): 41.0;
50.8; 67.1; 110.7; 123.7; 127.2; 128.4; 128.85, 128.88, 129.7; 131.2; 136.8; 137.4; 142.8; 146.3; 155.0;
156.0; 156.1. EI-MS: 433 (M+). Anal. calc. for C23H20ClN5O2 (433.89): C 63.67, H 4.65, N 16.14; found:
C 63.56, H 4.72, N 16.23.
tert-Butyl {(1S)-1-[1-(6-Chloropyridazin-3-yl)-1H-pyrazol-5-yl]-2-phenylethyl}carbamate (21j).
From 4b (0.173 g, 0.5 mmol), 18h (0.072 g, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol)
by G.P. A (reflux for 6 h): 0.108 g (54%) of 21j. M.p. 198–2018 (EtOH). [a]2D61=+36.6 (c=0.32,
CH2Cl2). IR (KBr): 3366, 1689 (C=O), 1525, 1429, 1422, 1251, 1169, 1021, 922, 838. H-NMR (CDCl3):
1.34 (s, t-BuO); 3.02–3.16 (m, HaÀC(2)); 3.27 (dd, J=5.7, 13.6, HbÀC(2)); 5.77 (br. s, HÀC(1), NH);
6.33 (s, HÀC(4’)); 7.07–7.16 (m, 2 H of Ph); 7.17–7.28 (m, 3 H of Ph); 7.63 (d, J=9.4, HÀC(5’’)); 7.64
(s, HÀC(3’)); 8.21 (br. d, J=9.4, HÀC(4’’)). 13C-NMR (CDCl3): 28.3; 40.8; 49.9; 79.7; 110.1; 123.2;
126.7; 128.4; 129.3; 130.6; 137.1; 142.3; 146.5; 154.5; 155.0; 155.8. Anal. calc. for C20H22ClN5O2
(399.87): C 60.07, H 5.55, N 17.51; found: C 60.05, H 5.64, N, 17.55.
Benzyl {(1S)-2-Phenyl-1-[1-(6-phenylpyridazin-3-yl)-1H-pyrazol-5-yl]ethyl}carbamate (21k). From
4a (0.190 g, 0.5 mmol), 18i (0.093 g, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol) by G.P.
A (reflux for 1.5 h): 0.185 g (78%) of 21k. M.p. 203–2068. [a]2D4 =+20.7 (c=0.50, CHCl3). IR (KBr):
1
3337, 1694 (C=O), 1538, 1427, 1396, 1264, 1051, 924, 802, 745, 688. H-NMR (CDCl3): 3.24–3.38 (m,
HÀC(2)); 5.04 (s, PhCH2O); 5.79–5.89 (m, HÀC(1)); 6.32 (d, J=1.5, HÀC(4’)); 6.50 (br. d, J=6.4,
NH); 7.05–7.13 (m, 2 H of Ph); 7.16–7.24 (m, 3 H of Ph); 7.27–7.40 (m, 5 H of Ph); 7.51–7.61 (m, 3
H of Ph); 7.64 (d, J=1.5, HÀC(3’)); 8.01 (d, J=9.0, HÀC(5’’)); 8.06–8.14 (m, 2 H of Ph); 8.28 (d,
J=9.0, HÀC(4’’)). 1H-NMR ((D6)DMSO): 2.86 (dd, J=10.2, 13.2, HaÀC(2)); 3.23 (dd, J=3.8, 13.6,
HbÀC(2)); 4.92 (s, PhCH2O); 5.97–6.07 (m, HÀC(1)); 6.65 (d, J=1.5, HÀC(4’)); 6.86 (br. s, NH);
7.16–7.42 (m, 9 H of Ph); 7.56–7.66 (m, 3 H of Ph); 7.85 (d, J=1.5, HÀC(3’)); 8.08–8.14 (m, 1 H of

Helvetica Chimica Acta – Vol. 89 (2006)
41
Ph); 8.20 (d, J=9.2, HÀC(5’’)); 8.22–8.26 (m, 2 H of Ph); 8.45 (d, J=9.2, HÀC(4’’)). 13C-NMR
((D6)DMSO): 41.8; 51.6; 66.1; 108.6; 122.1; 127.2; 127.8; 128.27; 128.35; 128.5; 128.9; 129.1; 130.01;
130.02; 131.1; 136.2; 137.9; 139.2; 142.9; 149.1; 156.3; 156.5; 158.3. EI-MS: 475 (M+). EI-HR-MS:
476.207780 (C29H26N5Oþ2 , [M+H]+; calc. 476.208650). Anal. calc. for C29H25N5O2 (475.54): C 73.25, H
5.30, N 14.73; found: C 72.92, H 5.38, N 14.34.
Benzyl {(1R,2R)-2-Hydroxy-1-(1-phenyl-1H-pyrazol-5-yl)propy}lcarbamate (23a). From 10 (181 mg,
0.5 mmol) and 18b (0.072 g, 0.5 mmol) by G.P. B (stirring at 808 for 6 h). CC (AcOEt/hexanes 1:1) gave
0.161 g (92%) of 23a. Oil. [a]2D4 =+37.05 (c=1.88, CHCl3). IR (NaCl): 3311, 1709 (C=O), 2598, 1503,
1455, 1399, 1272, 1063, 928, 766, 697. 1H-NMR (CDCl3): 1.08 (d, J=6.4, Me(3)); 1.85 (s, OH);
3.76–3.86 (m, HÀC(2)); 4.77–4.93 (m, HÀC(1)); 5.09 (s, PhCH2O); 5.44 (d, J=6.4, NH); 6.38 (d,
J=1.9, HÀC(4’)); 7.28–7.55 (m, 2 Ph); 7.63 (dd, J=0.5, 1.9, HÀC(3’)). 13C-NMR (CDCl3): 20.5; 53.7;
67.5; 69.4; 105.7; 126.5; 128.5; 128.7; 128.97; 129.02; 129.7; 136.6; 139.7; 140.3; 143.4; 156.7. EI-MS:
352 ([M+H]+). FAB-MS: 352 ([M+H]+). EI-HR-MS: 352.167200 (C20H22N3Oþ3 , calc. [M+H]+;
352.166117).
Benzyl {(1R,2R)-2-Hydroxy-1-[1-(6-phenylpyridazin-3-yl)-1H-pyrazol-5-yl]propyl}carbamate (23b).
From 10 (181 mg, 0.5 mmol), 18i (0.093 g, 0.5 mmol), and 37% aq. HCl soln. (2 drops, ca. 0.6 mmol) by
G.P. A (reflux for 2 h): 0.114 g (63%) of 23b. M.p. 210–2118. [a]2D5 =+30.0 (c=0.5, CHCl3). IR (KBr):
3510, 1696 (C=O), 1528, 1464, 1435, 1394, 1269, 1231, 1062, 920, 689. 1H-NMR (CDCl3): 1.33 (d,
J=6.0, Me(3)); 2.54 (s, OH); 4.40–4.51 (m, HÀC(2)); 5.08 (s, PhCH2O); 5.65 (dd, J=3.0, 8.7, HÀ
C(1)); 6.31 (d, J=8.8, NH); 6.52 (d, J=1.6, HÀC(4’)); 7.27–7.41 (m, Ph); 7.49–7.60 (m, 3 H of Ph);
7.72 (d, J=1.7, HÀC(3’)); 7.99 (d, J=8.9, HÀC(5’’)); 8.02–8.08 (m, 2 H of Ph); 8.25 (d, J=9.5, HÀ
1
C(4’’)). H-NMR ((D6)DMSO): 1.10 (d, J=6.0, Me(3)); 3.94–4.05 (m, HÀC(2)); 4.79 (d, J=5.7, OH);
4.99, 5.04 (2d, 1:1, J=12.8, PhCH2O); 5.82 (dd, J=4.1, 9.3, HÀC(1)); 6.66 (d, J=1.5, HÀC(4’));
7.27–7.39 (m, 4 H of Ph); 7.53 (d, J=9.8, HÀC(5’’)); 7.55–7.64 (m, 3 H of Ph); 7.81 (d, J=1.5, HÀ
C(3’)); 8.16–8.25 (m, 3 H of Ph); 8.46 (d, J=9.4, HÀC(4’’)). 13C-NMR (CDCl3): 21.1; 54.5; 66.4; 68.6;
109.9; 122.7; 127.7; 128.2; 128.5; 128.6; 129.2; 130.0; 131.1; 136.1; 137.9; 142.7; 146.7; 156.6; 157.0;
158.2. EI-MS: 411 ([MÀH2O]+). EI-HR-MS: 411.170300 (C24H21N5O2þ, calc. [MÀH2O]+; 411.169525).
Anal. calc. for C24H23N5O3 (429.47): C 67.12, H 5.40, N 16.31; found: C 67.00, H 5.51, N 16.15.
6. Benzyl [(1R,2R)1-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)-2-hydroxypropyl]carbamate (16). A
mixture of 10 (0.181 g, 0.5 mmol), 11c (54 mg, 0.5 mmol), EtOH (4 ml), and 37% aq. HCl soln. (3
drops, ca. 1 mmol) was heated under reflux for 6 h. After cooling, the precipitate was collected by filtra-
tion and washed with EtOH and Et2O to give the first portion of 16. The filtrate was evaporated and the
residue purified by CC (AcOEt/hexanes 1:1) to give a second portion of 16 which was crystallized from
CHCl3. Combined yield: 0.135 g (77%) of 16. M.p. 168–1748. [a]2D5 =À35.2 (c=0.5, CHCl3). IR (KBr):
1
3402, 2228 (CꢀN), 1695 (C=O), 1622, 1551, 1511, 1322, 1261, 1215, 1097, 691. H-NMR (CDCl3): 1.42
(d, J=6.4, Me(3)); 2.37 (d, J=2.6, OH); 4.46–4.59 (m, HÀC(1)); 5.12 (s, PhCH2O); 5.40 (dd, J=1.9,
8.7, HÀC(2)); 6.07 (d, J=8.7, NH); 7.06 (d, J=4.1, HÀC(6’)); 7.29–7.43 (m, Ph); 8.37 (s, HÀC(2’));
8.69 (d, J=4.1, HÀC(5’)). 13C-NMR (CDCl3): 20.9; 56.6; 65.8; 66.8; 82.1; 110.0; 114.2; 128.5; 128.7;
129.2; 137.7; 148.2; 150.9; 151.8; 154.5; 157.2. EI-MS: 352 ([M+H]+). Anal. calc. for C18H17N5O3
(351.36): C 61.53, H 4.88, N 19.93; found: C 61.59, H 4.95, N 19.96.
7. tert-Butyl [(1S)-2-Phenyl-1-(2-phenylpyrimidin-4-yl)ethyl]carbamate (17). A mixture of 4b (0.173
g, 0.5 mmol), 12 (0.117 g, 0.75 mmol), K2CO3 (0.070 g, 0.5 mmol), and EtOH (4 ml) was heated under
reflux for 6 h. The mixture was cooled and evaporated, and the residue purified by CC (AcOEt/hexanes
1:2): 0.050 g (27%) of 17. M.p. 114–1168. [a]D24 =À2.57 (c=0.50, CHCl3). IR(KBr): 3383, 2978, 1690
1
(C=O), 1568, 1559, 1514, 1389, 1169, 1018, 694. H-NMR (CDCl3): 1.44 (s, t-BuO); 3.13 (dd, J=7.9,
13.2, HaÀC(2)); 3.28 (dd, J=5.3, 13.2, HbÀC(2)); 4.93–5.11 (m, HÀC(1)); 5.62 (br. d, J=6.8, NH);
6.76 (d, J=4.9, HÀC(5’)); 6.98–7.09 (m, 2 H of Ph); 7.13–7.24 (m, 3 H of Ph); 7.46–7.56 (m, 3 H of
Ph); 8.41–8.51 (m, 2 H of Ph); 8.60 (d, J=4.9, HÀC(6’)). 13C-NMR (CDCl3): 28.8; 42.5; 56.9; 80.27;
117.6; 127.1; 128.7; 128.8; 129.0; 129.9; 131.2; 137.2; 137.9; 155.6; 157.6; 164.8; 168.5. EI-MS: 375
(M+). EI-HR-MS: 375.194777 (C23H25N3O2þ, M+; calc. 375.194677). Anal. calc. for C23H25N3O2
(375.46): C 73.57, H 6.71, N 11.19; found: C 73.82, H 6.98, N 11.05.
8. Compounds 22a–g and 24a,b: General Procedure. A mixture of N-[(benzyloxy)carbonyl]-pro-
tected amine 21a,c–e,g,h,k or 23a,b (0.5 mmol) in EtOH, THF, or EtOH/THF (10 ml) and 10% Pd/C

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Helvetica Chimica Acta – Vol. 89 (2006)
(40 mg) was hydrogenated (1 bar) at r.t. for 24 h. The mixture was filtered through a short pad of Celite®
and washed thoroughly with MeOH. The filtrate was evaporated when necessary, the product was puri-
fied by CC. Compounds 22a–g and 24a,b were prepared in this manner.
(1S)-2-Phenyl-1-(1H-pyrazol-5-yl)ethanamine (22a). From a mixture 21a/21’a (0.161 g, 0.5 mmol) in
EtOH, CC (CHCl3/MeOH 10 :1) gave 0.086 g (92%) of 22a. Oil. [a]2D4 =À9.00 (c=1.54, CHCl3). IR
(NaCl): 3177, 2922, 1602, 1584, 1495, 1454, 1380, 927, 768, 700. 1H-NMR (CDCl3): 2.86 (dd, J=8.7,
13.6, HaÀC(2)); 3.17 (dd, J=4.9, 13.6, HbÀC(2)); 4.00 (br. s, NH2); 4.35 (dd, J=4.9, 8.7, HÀC(1));
6.19 (d, J=1.9, HÀC(4’)); 7.16–7.40 (m, Ph, HÀN(1’)); 7.51 (d, J=2.3, HÀC(3’)). 1H-NMR
((D6)DMSO): 2.04 (br. s, NH2); 2.81 (dd, J=7.9, 13.2, HaÀC(2)); 3.00 (dd, J=6.0, 13.2, HbÀC(2));
4.11 (dd, J=6.0, 7.9, HÀC(1)); 6.11 (s, HÀC(4’)); 7.13–7.28 (m, Ph); 7.45 (br. s, HÀC(3’)); 12.45 (br.
s, HÀN(1’)). 13C-NMR (CDCl3): 45.2; 51.1; 102.6; 127.0; 128.9; 129.8; 133.9; 138.8; 152.2. FAB-MS:
188 ([M+H]+).
(1S)-2-Phenyl-1-(1-phenyl-1H-pyrazol-5-yl)ethanamine (22b). From 21c (0.199 g, 0.5 mmol) in
EtOH: 0.108 g (82%) of 22b. Oil. [a]2D1 =À12.1 (c=1.97, CHCl3). IR (NaCl): 3365, 3062, 3028, 2922,
1599, 1503, 1454, 1398, 1199, 1072, 924, 697. 1H-NMR (CDCl3): 1.62 (br. s, NH2); 2.81 (dd, J=8.3,
13.4, HaÀC(2)); 3.01 (dd, J=5.7, 13.5, HbÀC(2)); 4.26 (dd, J=5.7, 8.1, HÀC(1)); 6.45 (d, J=1.5, HÀ
C(4’)); 6.94–7.03 (m, 2 H of Ph); 7.14–7.24 (m, 3 H of Ph); 7.28–7.35 (m, 2 H of Ph); 7.37–7.48 (m, 3
1
H of Ph); 7.63 (d, J=1.5, HÀC(3’)). H-NMR ((D6)DMSO): 2.04 (br. s, NH2); 2.82 (dd, J=7.2, 13.2,
HaÀC(2)); 2.87 (dd, J=6.8, 13.2, HbÀC(2)); 4.05 (dd, J=6.8, 7.2, HÀC(1)); 6.53 (d, J=1.9, HÀC(4’));
6.90–6.95 (m, 2 H of Ph); 7.09–7.20 (m, 3 H of Ph); 7.29–7.34 (m, 2 H of Ph); 7.38–7.50 (m, 3 H of
Ph); 7.57 (d, J=1.9, HÀC(4’)). 13C-NMR (CDCl3): 45.3; 49.7; 104.3; 126.3; 127.1; 128.7; 128.9; 129.5;
129.6; 138.2; 140.1; 140.3. EI-MS: 264 ([M+H]+). EI-HR-MS: 264.150460 (C17H18Nþ3 , [M+H]+; calc.
264.150073).
(1S)-1-[1-(4-Aminophenyl)-1H-pyrazol-5-yl]-2-phenylethanamine (22c). From 21d (0.221 g, 0.5
mmol) in EtOH. CC (CHCl3/MeOH 10 :1) gave 0.132 g (95%) of 22c. Oil. [a]2D4 =À14.2 (c=1.38,
1
CHCl3). IR (NaCl): 3343, 3217, 2923, 1627, 1609, 1522, 1400, 1294, 1172, 1078, 929, 834, 701. H-NMR
(CDCl3): 1.81 (br. s, NH2ÀC(1)); 2.78 (dd, J=8.3, 13.2, HaÀC(2)); 2.99 (dd, J=5.7, 13.6, HbÀC(2));
3.80 (br. s, ArNH2); 4.17 (dd, J=5.7, 8.3, HÀC(1)); 6.37 (d, J=1.9, HÀC(4’)); 6.59–6.68 (m, 2 H of
C6H4); 6.94–7.06 (m, 2 H of Ph, 2 H of C6H4); 7.14–7.28 (m, 3 H of Ph); 7.57 (d, J=1.9, HÀC(3’)).
13C-NMR (CDCl3): 45.1; 49.6; 103.5; 115.4; 127.0; 127.7; 128.9; 129.7; 130.8; 138.4; 139.7; 147.3; 147.8.
EI-MS: 278 (M+). EI-HR-MS: 278.143500 (C17H18Nþ4 , M+; calc. 278.153147).
(1S)-1-[1-(4-Methoxyphenyl)-1H-pyrazol-5-yl]-2-phenylethanamine (22d). From 21e (0.214 g, 0.5
mmol) in EtOH: 0.144 g (98%) of 22d. Oil. [a]2D4 =À4.18 (c=0.96, CHCl3). IR (NaCl): 3357, 2930,
1
2838, 1607, 1518, 1455, 1301, 1251, 1027, 837, 701. H-NMR (CDCl3): 2.96 (dd, J=7.2, 13.2, HaÀC(2));
3.06 (dd, J=6.8, 13.2, HbÀC(2)); 3.51 (br. s, NH2); 3.83 (s, MeO); 4.23 (t, J=7.2, HÀC(1)); 6.56 (d,
J=1.9, HÀC(4’)); 6.86–6.92 (m, 2 H of C6H4); 6.93–6.99 (m, of C6H4); 7.04–7.11 (m, 2 H of Ph);
7.18–7.24 (m, 3 H of Ph); 7.59 (d, J=1.9, HÀC(3’)). 13C-NMR (CDCl3): 44.3; 49.6; 55.9; 104.5; 114.6;
127.3; 127.9; 129.0; 129.7; 132.6; 137.3; 140.1; 145.6; 160.0. EI-MS: 294 ([M+H]+). EI-HR-MS
294.161030 (C18H20N3O+, [M+H]+; calc. 294.160637).
(1S)-2-Phenyl-1-[1-(pyridin-2-yl)-1H-pyrazol-5-yl]ethanamine (22e). From 21g (0.199 g, 0.5 mmol)
in EtOH/THF 4 :1. CC (CHCl3/MeOH 10 :1) gave 0.112 g (85%) of 22e. Oil. [a]2D1 =À31.4 (c=2.75,
1
CHCl3). IR (NaCl): 3362, 3024, 2923, 1591, 1578, 1474, 1435, 1386, 1202, 1081, 922, 787, 699. H-NMR
(CDCl3): 1.91 (br. s, NH2); 2.91 (dd, J=9.0, 13.6, HaÀC(2)); 3.29 (dd, J=4.9, 13.6, HbÀC(2)); 5.02 (dd,
J=4.9, 9.0, HÀC(1)); 6.45 (d, J=1.5, HÀC(4’)); 7.14–7.40 (m, Ph, HÀC(5’’)); 7.63 (d, J=1.5, HÀC(3’));
7.79–7.86 (m, HÀC(3’’)); 7.88–7.94 (m, HÀC(4’’)); 8.45–8.49 (m, HÀC(6’’)). 13C-NMR (CDCl3): 43.7;
50.2; 106.5; 117.0; 121.9; 126.9; 128.8; 129.7; 139.1; 139.4; 141.1; 147.8; 150.0; 153.9. EI-MS: 264 (M+).
EI-HR-MS: 264.138220 (C16H16Nþ4 , M+; calc. 264.136159).
(1S)-2-Phenyl-1-[1-(pyrimidin-2-yl)-1H-pyrazol-5-yl]ethanamine (22f). From 21h (0.200 g, 0.5
mmol) in EtOH. CC (CHCl3/MeOH 10 :1) gave 0.072 g (69%) of 22f. Oil. [a]2D1 =À55.8 (c=1.25,
1
CHCl3). IR (NaCl): 3253, 2926, 1587, 1525, 1453, 1420, 799, 700. H-NMR (CDCl3): 2.01 (br. s, NH2);
2.92 (dd, J=9.0, 13.6, HaÀC(2)); 3.29 (dd, J=4.5, 13.6, HbÀC(2)); 5.07 (dd, J=4.5, 9.0, HÀC(1)); 6.51
(d, J=1.5, HÀC(4’)); 7.18–7.41 (m, Ph, HÀC(5’’)); 7.73 (d, J=1.5, HÀC(3’)); 8.82 (d, J=4.9, HÀ

Helvetica Chimica Acta – Vol. 89 (2006)
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C(4’’), HÀC(6’’)). 13C-NMR (CDCl3): 43.7; 50.4; 107.6; 119.0; 127.0; 128.9; 129.7; 139.0; 142.5; 151.2;
158.4; 159.1. EI-MS: 265 (M+), 264 ([MÀH]+). EI-HR-MS: 265.133070 (C15H15Nþ5 , M+; calc.
265.132746).
(1S)-2-Phenyl-1-[1-(6-phenylpyridazin-3-yl)-1H-pyrazol-5-yl]ethanamine (22g). From 21k (0.238 g,
0.5 mmol) in THF. CC (CHCl3/MeOH 20 :1) and then MPLC (CHCl3/MeOH 30 :1) gave 0.120 g
(70%) of 22g. Oil. [a]2D4 =À36.9 (c=1.78, CHCl3). IR (NaCl): 3360, 3061, 2924, 1535, 1464, 1453, 1431,
1396, 921, 747, 697. 1H-NMR (CDCl3): 2.12 (br. s, NH2); 3.03 (dd, J=8.7, 13.3, HaÀC(2)); 3.31 (dd,
J=5.2, 13.3, HbÀC(2)); 5.26 (dd, J=5.2, 8.7, HÀC(1)); 6.57 (d, J=1.8, HÀC(4’)); 7.15–7.30 (m, Ph);
7.49–7.59 (m, 3 H of Ph); 7.72 (d, J=1.8, HÀC(3’)); 7.98 (d, J=9.2, HÀC(5’’)); 8.05–8.13 (m, 2 H of
Ph); 8.18 (d, J=9.2, HÀC(4’’)). 13C-NMR (CDCl3): 43.9; 50.3; 107.8; 121.8; 126.95; 126.96; 127.4;
128.8; 129.5; 129.9; 130.6; 136.1; 138.8; 142.4; 150.2; 156.1; 158.4. EI-MS: 341 (M+). EI-HR-MS:
341.165120 (C21H19Nþ5 , M+; calc. 341.164046).
(1R,2R)-1-Amino-1-(1-phenyl-1H-pyrazol-5-yl)propan-2-ol (24a). From 23a in EtOH. CC (CHCl3/
MeOH 10 :1) gave 0.090 g (83%) of 24a. Oil. [a]2D6 =+9.0 (c=0.5, CHCl3). IR (NaCl): 3356, 1595,
1530, 1501, 1455, 1398, 1201, 1115, 1067, 1007, 928, 768. 1H-NMR (CDCl3): 0.99 (d, J=6.0, Me(3));
2.48 (s, OH, NH2); 3.66 (d, J=7.9, HÀC(1)); 3.75 (dq, J=6.0, 7.9, HÀC(2)); 6.32 (d, J=1.9, HÀ
C(4’)); 7.39–7.52 (m, Ph); 7.61 (dd, J=0.5, 1.9, HÀC(3’)). 13C-NMR (CDCl3): 20.1; 54.0; 71.0; 104.0;
126.5; 129.0; 129.7; 139.8; 140.6; 146.1. EI-MS: 218 ([MÀH]+). FAB-MS: 218 ([MÀH]+). EI-HR-MS:
218.129900 (C12H16N3O+, [MÀH]+; calc. 218.129337).
(1R,2R)-1-Amino-1-[1-(6-phenylpyridazin-3-yl)-1H-pyrazol-3-yl]propan-2-ol (24b). From 23b in
EtOH/THF 3 :7. CC (CHCl3/MeOH 8 :1) gave 0.094 g (64%) of 24b. M.p. 113–1188. [a]2D6 =+2.0
(c=0.5, CHCl3). IR (KBr): 3447, 1634, 1585, 1561, 1533, 1461, 1432, 1393, 1202, 1026, 937, 781, 743,
1
687. H-NMR (CDCl3): 1.21 (d, J=6.0, Me(3)); 2.41 (br. s, OH, NH2); 4.06 (dq, J=6.1, 7.7, HÀC(2));
4.55 (d, J=7.7, HÀC(1)); 6.47 (d, J=1.7, HÀC(4’)); 7.49–7.61 (m, 3 H of Ph); 7.74 (d, J=1.7, HÀ
C(3’)); 8.03 (d, J=9.2, HÀC(5’’)); 8.06–8.11 (m, 2 H of Ph); 8.26 (d, J=9.2, HÀC(4’’)). 13C-NMR
(CDCl3): 20.4; 54.6; 69.3; 107.7; 122.1; 127.2; 127.4; 129.6; 130.7; 135.9; 142.6; 148.2; 156.0; 158.6. EI-
MS: 296 ([MÀH]+). FAB-MS: 296 ([MÀH]+). EI-HR-MS: 296.152001 (C16H18N5O+, [MÀH]+; calc.
296.151135).
9. X-Ray Crystal-Structure Determination of 15b. A prismatic colorless crystal with dimensions
0.80×0.35×0.20 mm was used for data collection at r.t. on a Nonius-Kappa-CCD diffractometer with
graphite monochromated MoKa radiation in the w scan mode. The q range was 2.55–26.028. The data
were processed with the DENZO [20] program. The number of integrated, symmetry-independent,
and observed (F2 >2.0sF2) reflections were 26511, 2181, and 1589, respectively. The structure was solved
by direct methods with SIR97 [21]. We employed full-matrix least-squares refinements on F magnitudes
with anisotropic displacement factors for all non-H-atoms. The positions of H-atoms bonded to C(1),
C(2), and N(4) were obtained from the difference Fourier map while the remaining were calculated.
The parameters of H-atoms were not refined. In the final cycle of the refinement, we used 1949 reflec-
tions (included were those less-than reflections for which FC was greater than FO) and 226 parameters.
The final R, Rw, and S were 0.061, 0.034, and 1.479, resp. The residual density in final difference map
was max. 0.203 and min. À0.300 e/Å3. The Xtal3.6 [22] system of crystallographic programs was used
for the structure refinement and interpretation. ORTEPII [23] was used to produce molecular graphics.
CCDC-268823 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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Received August 26, 2005